J.B.C. de Klerk (Johannes)http://repub.eur.nl/ppl/7307/
List of Publicationsenhttp://repub.eur.nl/eur_signature.pnghttp://repub.eur.nl/
RePub, Erasmus University Repository574-586 Mutations in PCBD1 cause hypomagnesemia and renal magnesium wastinghttp://repub.eur.nl/pub/64233/
Sat, 01 Mar 2014 00:00:01 GMT<div>S. Ferrè</div><div>J.H.F. de Baaij</div><div>P. Ferreira</div><div>R. Germann</div><div>J.B.C. de Klerk</div><div>A.P.M. Lavrijsen</div><div>F. van Zeeland</div><div>H. Venselaar</div><div>L.A.J. Kluijtmans</div><div>J.G. Hoenderop</div><div>R.J.M. Bindels</div>
Mutations in PCBD1 are causative for transient neonatal hyperphenylalaninemia and primapterinuria (HPABH4D). Until now, HPABH4D has been regarded as a transient and benign neonatal syndrome without complications in adulthood. In our study of three adult patients with homozygous mutations in the PCBD1 gene, two patients were diagnosed with hypomagnesemia and renal Mg 2+ loss, and two patients developed diabetes with characteristics of maturity onset diabetes of the young (MODY), regardless of serum Mg2+ levels. Our results suggest that these clinical findings are related to the function of PCBD1 as a dimerization cofactor for the transcription factor HNF1B. Mutations in the HNF1B gene have been shown to cause renal malformations, hypomagnesemia, and MODY. Gene expression studies combined with immunohistochemical analysis in the kidney showed that Pcbd1 is expressed in the distal convoluted tubule (DCT), where Pcbd1 transcript levels are upregulated by a low Mg2+-containing diet. Overexpression in a human kidney cell line showed that wild-type PCBD1 binds HNF1B to costimulate the FXYD2 promoter, the activity of which is instrumental in Mg2+ reabsorption in the DCT. Of seven PCBD1 mutations previously reported in HPABH4D patients, five mutations caused proteolytic instability, leading to reduced FXYD2 promoter activity. Furthermore, cytosolic localization of PCBD1 increased when coexpressed with HNF1B mutants. Overall, our findings establish PCBD1 as a coactivator of the HNF1B-mediated transcription necessary for fine tuning FXYD2 transcription in the DCT and suggest that patients with HPABH4D should be monitored for previously unrecognized late complications, such as hypomagnesemia and MODY diabetes. CopyrightGenetic basis of hyperlysinemiahttp://repub.eur.nl/pub/61443/
Thu, 11 Apr 2013 00:00:01 GMT<div>S.M. Houten</div><div>H. Te Brinke</div><div>S. Denis</div><div>J.P.N. Ruiter</div><div>A.C. Knegt</div><div>J.B.C. de Klerk</div><div>P. Augoustides-Savvopoulou</div><div>J. Häberle</div><div>M.R. Baumgartner</div><div>T. Coşkun</div><div>J. Zschocke</div><div>J.O. Sass</div><div>B.T. Poll-The</div><div>R.J.A. Wanders</div><div>M. Duran</div>
Background: Hyperlysinemia is an autosomal recessive inborn error of L-lysine degradation. To date only one causal mutation in the AASS gene encoding aminoadipic semialdehyde synthase has been reported. We aimed to better define the genetic basis of hyperlysinemia. Methods. We collected the clinical, biochemical and molecular data in a cohort of 8 hyperlysinemia patients with distinct neurological features. Results: We found novel causal mutations in AASS in all affected individuals, including 4 missense mutations, 2 deletions and 1 duplication. In two patients originating from one family, the hyperlysinemia was caused by a contiguous gene deletion syndrome affecting AASS and PTPRZ1. Conclusions: Hyperlysinemia is caused by mutations in AASS. As hyperlysinemia is generally considered a benign metabolic variant, the more severe neurological disease course in two patients with a contiguous deletion syndrome may be explained by the additional loss of PTPRZ1. Our findings illustrate the importance of detailed biochemical and genetic studies in any hyperlysinemia patient.Risk stratification by residual enzyme activity after newborn screening for medium-chain acyl-CoA dehyrogenase deficiency: Data from a cohort studyhttp://repub.eur.nl/pub/60857/
Mon, 28 May 2012 00:00:01 GMT<div>C.M.L. Touw</div><div>G.P. Smit</div><div>M. de Vries</div><div>J.B.C. de Klerk</div><div>A.M. Bosch</div><div>G. Visser</div><div>M.F. Mulder</div><div>M.E. Rubio-Gozalbo</div><div>L.H. Elvers</div><div>K.E. Niezen-Koning</div><div>R.J.A. Wanders</div><div>H.R. Waterham</div><div>D.J. Reijngoud</div><div>T.G.J. Derks</div>
Background. Since the introduction of medium-chain acyl coenzyme A dehydrogenase (MCAD) deficiency in population newborn bloodspot screening (NBS) programs, subjects have been identified with variant ACADM (gene encoding MCAD enzyme) genotypes that have never been identified in clinically ascertained patients. It could be hypothesised that residual MCAD enzyme activity can contribute in risk stratification of subjects with variant ACADM genotypes. Methods. We performed a retrospective cohort study of all patients identified upon population NBS for MCAD deficiency in the Netherlands between 2007-2010. Clinical, molecular, and enzymatic data were integrated. Results. Eighty-four patients from 76 families were identified. Twenty-two percent of the subjects had a variant ACADM genotype. In patients with classical ACADM genotypes, residual MCAD enzyme activity was significantly lower (median 0%, range 0-8%) when compared to subjects with variant ACADM genotypes (range 0-63%; 4 cases with 0%, remainder 20-63%). Patients with (fatal) neonatal presentations before diagnosis displayed residual MCAD enzyme activities <1%. After diagnosis and initiation of treatment, residual MCAD enzyme activities <10% were associated with an increased risk of hypoglycaemia and carnitine supplementation. The prevalence of MCAD deficiency upon screening was 1/8,750 (95% CI 1/7,210-1/11,130). Conclusions. Determination of residual MCAD enzyme activity improves our understanding of variant ACADM genotypes and may contribute to risk stratification. Subjects with variant ACADM genotypes and residual MCAD enzyme activities <10% should be considered to have the same risks as patients with classical ACADM genotypes. Parental instructions and an emergency regimen will remain principles of the treatment in any type of MCAD deficiency, as the effect of intercurrent illness on residual MCAD enzyme activity remains uncertain. There are, however, arguments in favour of abandoning the general advice to avoid prolonged fasting in subjects with variant ACADM genotypes and >10% residual MCAD enzyme activity.A series of pregnancies in women with inherited metabolic diseasehttp://repub.eur.nl/pub/33624/
Thu, 15 Sep 2011 00:00:01 GMT<div>J.G. Langendonk</div><div>J.C. Roos</div><div>L. Angus</div><div>M. Williams</div><div>F.P. Karstens</div><div>J.B.C. de Klerk</div><div>C. Maritz</div><div>T. Ben-Omran</div><div>C. Williamson</div><div>R.H. Lachmann</div><div>E. Murphy</div>
In this case series we report 12 pregnancies, in women treated at four centres, illustrating some of the issues that may be encountered during pregnancy by women with inherited metabolic disease. We discuss how specific pregnancy, labour and delivery issues for mothers with methylmalonic acidemia, homocystinuria, propionic acidemia, glutaric acidemia type 1, ornithine transcarbamylase (OTC) deficiency and 3-hydroxy-3-methylglutaric(HMG)-CoA lyase deficiency were managed and the outcome for the mother and child in each case. Eight of the 12 pregnancies resulted in the successful delivery of a liveborn infant. Several women experienced decompensation of their condition during pregnancy or the post-partum period. There was one maternal death in a women with 3-hydroxy-3-methylglutaric(HMG)-CoA lyase deficiency. Pre-pregnancy counselling and co-management of high risk medical patients by obstetricians and specialist physicians with an understanding of the relationship between pregnancy and inherited metabolic disease is essential.Long-term follow-up and treatment in nine boys with X-linked creatine transporter defecthttp://repub.eur.nl/pub/25734/
Tue, 10 May 2011 00:00:01 GMT<div>J.M. van de Kamp</div><div>P.J.W. Pouwels</div><div>F.K. Aarsen</div><div>L.W. ten Hoopen</div><div>D.L. Knol</div><div>J.B.C. de Klerk</div><div>I.F.M. de Coo</div><div>J.G.M. Huijmans</div><div>C. Jakobs</div><div>M.S. van der Knaap</div><div>G.S. Salomons</div><div>G.M.S. Mancini</div>
The creatine transporter (CRTR) defect is a recently discovered cause of X-linked intellectual disability for which treatment options have been explored. Creatine monotherapy has not proved effective, and the effect of treatment with L-arginine is still controversial. Nine boys between 8 months and 10 years old with molecularly confirmed CRTR defect were followed with repeated1H-MRS and neuropsychological assessments during 4-6 years of combination treatment with creatine monohydrate, L-arginine, and glycine. Treatment did not lead to a significant increase in cerebral creatine content as observed with H1-MRS. After an initial improvement in locomotor and personal-social IQ subscales, no lasting clinical improvement was recorded. Additionally, we noticed an age-related decline in IQ subscales in boys affected with the CRTR defect. Hemoglobin precipitation greatly improves 4-methylumbelliferone-based diagnostic assays for lysosomal storage diseases in dried blood spotshttp://repub.eur.nl/pub/34256/
Sat, 01 Jan 2011 00:00:01 GMT<div>L.F. Oemardin</div><div>A.M. Boer</div><div>G.J.G. Ruijter</div><div>A.T. van der Ploeg</div><div>J.B.C. de Klerk</div><div>A.J.J. Reuser</div><div>F.W. Verheijen</div>
Derivatives of 4-methylumbelliferone (4MU) are favorite substrates for the measurement of lysosomal enzyme activities in a wide variety of cell and tissue specimens. Hydrolysis of these artificial substrates at acidic pH leads to the formation of 4-methylumbelliferone, which is highly fluorescent at a pH above 10.When used for the assay of enzyme activities in dried blood spots the light emission signal can be very low due to the small sample size so that the patient and control ranges are not widely separated. We have investigated the hypothesis that quenching of the fluorescence by hemoglobin leads to appreciable loss of signal and we show that the precipitation of hemoglobin with trichloroacetic acid prior to the measurement of 4-methylumbelliferone increases the height of the output signal up to eight fold. The modified method provides a clear separation of patients' and controls' ranges for ten different lysosomal enzyme assays in dried blood spots, and approaches the conventional leukocyte assays in outcome quality. Tyrosine hydroxylase deficiency: A treatable disorder of brain catecholamine biosynthesishttp://repub.eur.nl/pub/27454/
Tue, 01 Jun 2010 00:00:01 GMT<div>M.A. Willemsen</div><div>M.M. Verbeek</div><div>E.J. Kamsteeg</div><div>J.F. de Rijk-Van Andel</div><div>A. Aeby</div><div>N. Blau</div><div>A.B. Burlina</div><div>M.A. Donati</div><div>B. Geurtz</div><div>P.J. Grattan-Smith</div><div>M. Haeussler</div><div>G.F. Hoffmann</div><div>H. Jung</div><div>J.B.C. de Klerk</div><div>M.S. van der Knaap</div><div>F. Kok</div><div>V. Leuzzi</div><div>P. de Lonlay</div><div>A. Megarbane</div><div>H. Monaghan</div><div>W.O. Renier</div><div>P. Rondot</div><div>M.M. Ryan</div><div>J. Seeger</div><div>J.A.M. Smeitink</div><div>G.C. Steenbergen-Spanjers</div><div>E. Wassmer</div><div>B. Weschke</div><div>F.A. Wijburg</div><div>B. Wilcken</div><div>D.I. Zafeiriou</div><div>R.A. Wevers</div>
Tyrosine hydroxylase deficiency is an autosomal recessive disorder resulting from cerebral catecholamine deficiency. Tyrosine hydroxylase deficiency has been reported in fewer than 40 patients worldwide. To recapitulate all available evidence on clinical phenotypes and rational diagnostic and therapeutic approaches for this devastating, but treatable, neurometabolic disorder, we studied 36 patients with tyrosine hydroxylase deficiency and reviewed the literature. Based on the presenting neurological features, tyrosine hydroxylase deficiency can be divided in two phenotypes: an infantile onset, progressive, hypokinetic-rigid syndrome with dystonia (type A), and a complex encephalopathy with neonatal onset (type B). Decreased cerebrospinal fluid concentrations of homovanillic acid and 3-methoxy-4- hydroxyphenylethylene glycol, with normal 5-hydroxyindoleacetic acid cerebrospinal fluid concentrations, are the biochemical hallmark of tyrosine hydroxylase deficiency. The homovanillic acid concentrations and homovanillic acid/5-hydroxyindoleacetic acid ratio in cerebrospinal fluid correlate with the severity of the phenotype. Tyrosine hydroxylase deficiency is almost exclusively caused by missense mutations in the TH gene and its promoter region, suggesting that mutations with more deleterious effects on the protein are incompatible with life. Genotype-phenotype correlations do not exist for the common c.698G>A and c.707T>C mutations. Carriership of at least one promotor mutation, however, apparently predicts type A tyrosine hydroxylase deficiency. Most patients with tyrosine hydroxylase deficiency can be successfully treated with l-dopa. Erratum: Prediction of outcome in isolated methylmalonic acidurias: Combined use of clinical and biochemical parameters (J Inherit Metab Dis (2009) (DOI 10.1007/s10545-009-1189-6))http://repub.eur.nl/pub/19611/
Tue, 01 Dec 2009 00:00:01 GMT<div>F. Hörster</div><div>S.F. Garbade</div><div>T. Zwickler</div><div>H.I. Aydin</div><div>O.A. Bodamer</div><div>A.B. Burlina</div><div>A. Das</div><div>J.B.C. de Klerk</div><div>C. Dionisi-Vici</div><div>S. Geb</div><div>G. Gökcay</div><div>N. Guffon</div><div>E.M. Maier</div><div>E. Morava</div><div>J.H. Walter</div><div>B. Schwahn</div><div>F.A. Wijburg</div><div>M. Lindner</div><div>S. Grünewald</div><div>M.R. Baumgartner</div><div>S. Kölker</div>
Prediction of outcome in isolated methylmalonic acidurias: Combined use of clinical and biochemical parametershttp://repub.eur.nl/pub/24203/
Thu, 30 Jul 2009 00:00:01 GMT<div>F. Hörster</div><div>S.F. Garbade</div><div>T. Zwickler</div><div>M. Lindner</div><div>S. Kölker</div><div>H.I. Aydin</div><div>O.A. Bodamer</div><div>A.B. Burlina</div><div>A. Das</div><div>J.B.C. de Klerk</div><div>C. Dionisi-Vici</div><div>S. Geb</div><div>G. Gökcay</div><div>N. Guffon</div><div>E.M. Maier</div><div>E. Morava</div><div>J.H. Walter</div><div>B. Schwahn</div><div>F.A. Wijburg</div><div>S. Grünewald</div><div>M.R. Baumgartner</div>
Objectives: Isolated methylmalonic acidurias (MMAurias) are caused by deficiency of methylmalonyl-CoA mutase or by defects in the synthesis of its cofactor 5′-deoxyadenosylcobalamin. The aim of this study was to evaluate which parameters best predicted the long-term outcome. Methods: Standardized questionnaires were sent to 20 European metabolic centres asking for age at diagnosis, birth decade, diagnostic work-up, cobalamin responsiveness, enzymatic subgroup (mut0, mut-, cblA, cblB) and different aspects of long-term outcome. Results: 273 patients were included. Neonatal onset of the disease was associated with increased mortality rate, high frequency of developmental delay, and severe handicap. Cobalamin non-responsive patients with neonatal onset born in the 1970s and 1980s had a particularly poor outcome. A more favourable outcome was found in patients with late onset of symptoms, especially when cobalamin responsive or classified as mut-. Prevention of neonatal crises in pre-symptomatically diagnosed newborns was identified as a protective factor concerning handicap. Chronic renal failure manifested earlier in mut0patients than in other enzymatic subgroups. Conclusion: Outcome in MMAurias is best predicted by the enzymatic subgroup, cobalamin responsiveness, age at onset and birth decade. The prognosis is still unfavourable in patients with neonatal metabolic crises and non-responsiveness to cobalamin, in particular mut0patients. Phenylalanine tolerance can already reliably be assessed at the age of 2 years in patients with PKUhttp://repub.eur.nl/pub/25020/
Fri, 09 Jan 2009 00:00:01 GMT<div>F.J. van Spronsen</div><div>M. Rijn</div><div>B. Dorgelo</div><div>M. Hoeksma</div><div>A.M. Bosch</div><div>M.F. Mulder</div><div>J.B.C. de Klerk</div><div>T.J. de Koning</div><div>M.E. Rubio-Gozalbo</div><div>M. de Vries</div><div>P.H. Verkerk</div>
Background: The clinical severity of phenylalanine hydroxylase deficiency is usually defined by either pre-treatment phenylalanine (Phe) concentration or Phe tolerance at 5 years of age. So far, little is known about the course of Phe tolerance or the ability of both pre-treatment Phe and Phe tolerance at early age to predict Phe tolerance at later age. Aim: This study was conducted to investigate the course of the individual Phe tolerance and to assess the predictive value of both the pre-treatment Phe concentration and Phe tolerance at 1 and 6 months and 1, 2, 3 and 5 years for Phe tolerance at 10 years of age. Method: Data on blood Phe concentration, prescribed Phe intake and weight of 213 early and continuously treated Dutch PKU patients up to 10 years of age were collected. Data acquired under good metabolic control were used in the study. Tolerance was expressed in mg/day and mg/kg per day. Results: Data at 1 and 6 months and at 1, 2, 3 and 5 years of 61, 58, 59, 57, 56 and 59 patients were included for comparison with the Phe tolerance at 10 years. Phe tolerances (mg/kg per day) at 2, 3 and 5 years showed a clear correlation with the tolerance at 10 years of age (r = 0.608, r = 0.725 and r = 0.661). Results for tolerance expressed as mg/day were comparable. Pre-treatment Phe concentrations did not correlate significantly with the tolerance. Conclusion: Pre-treatment Phe is unreliable but Phe tolerance is a reliable predictor of the tolerance at 10 years of age, starting at 2 years of age. Brain abnormalities in a case of malonyl-CoA decarboxylase deficiencyhttp://repub.eur.nl/pub/73002/
Wed, 01 Feb 2006 00:00:01 GMT<div>M.C.Y. de Wit</div><div>I.F.M. de Coo</div><div>E. Verbeek</div><div>R. Schot</div><div>G.C. Schoonderwoerd</div><div>M. Duran</div><div>J.B.C. de Klerk</div><div>J.G.M. Huijmans</div><div>M.H. Lequin</div><div>F.W. Verheijen</div><div>G.M.S. Mancini</div>
Malonyl-CoA decarboxylase (MCD) deficiency is an extremely rare inborn error of metabolism that presents with metabolic acidosis, hypoglycemia, and/or cardiomyopathy. Patients also show neurological signs and symptoms that have been infrequently reported. We describe a girl with MCD deficiency, whose brain MRI shows white matter abnormalities and additionally diffuse pachygyria and periventricular heterotopia, consistent with a malformation of cortical development. MLYCD-gene sequence analysis shows normal genomic sequence but no messenger product, suggesting an abnormality of transcription regulation. Our patient has strikingly low appetite, which is interesting in the light of the proposed role of malonyl-CoA in the regulation of feeding control, but this remains to be confirmed in other patients. Considering the incomplete understanding of the role of metabolic pathways in brain development, patients with MCD deficiency should be evaluated with brain MRI and unexplained malformations of cortical development should be reason for metabolic screening.The intake of total protein, natural protein and protein substitute and growth of height and head circumference in Dutch infants with phenylketonuriahttp://repub.eur.nl/pub/55265/
Thu, 01 Dec 2005 00:00:01 GMT<div>M. Hoeksma</div><div>M. Rijn</div><div>P.H. Verkerk</div><div>A.M. Bosch</div><div>M.F. Mulder</div><div>J.B.C. de Klerk</div><div>T.J. de Koning</div><div>M.E. Rubio-Gozalbo</div><div>M. de Vries</div><div>P.J.J. Sauer</div><div>F.J. van Spronsen</div>
In a previous study, Dutch children with phenylketonuria (PKU) were found to be slightly shorter than their healthy counterparts. In the literature, it has been hypothesized that a higher protein intake is necessary to optimize growth in PKU patients. The study aimed to investigate whether protein intake (total, natural and protein substitute) in this group might be an explanatory factor for the observed growth. Growth of height and head circumference and dietary data on protein intake (total, natural and protein substitute) from 174 Dutch PKU patients born between 1974 and 1996 were analysed retrospectively for the patients' first 3 years of life. Analyses were corrected for energy intake during the first year of life and for the clinical severity of the deficiency of phenylalanine hydroxylase by means of plasma phenylalanine concentration at birth. Neither protein nor energy intake correlated with height growth. A positive, statistically significant relation between head circumference growth and natural protein and total protein intake was found, but not with the intake of the protein substitute or energy. Therefore, this study suggests that improvement of the protein substitute rather than an increase of total protein intake may be important in optimizing head circumference growth in PKU patients.Increasing fat in the diet does not improve muscle performance in patients with mitochondrial myopathy due to complex I deficiencyhttp://repub.eur.nl/pub/55618/
Sat, 01 Jan 2005 00:00:01 GMT<div>K. Meer</div><div>M.J. Roef</div><div>J.B.C. de Klerk</div><div>H.D. Bakker</div><div>G.P. Smit</div><div>B.T. Poll-The</div>
Four myopathic patients with complex I deficiency followed diets containing 55 energy per cent (En%) as fat or 25 En% as fat, both for three weeks. Maximal workload and muscle force were not different on either diet. Exercise endurance time, oxygen consumption and lactate levels were also not different, but one patient had diminished endurance time on 25 En% as fat. Our observations do not support the use of increasing the fat in the diet of patients with mitochondrial complex I deficiency.Pearson syndrome and the role of deletion dimers and duplications in the mtDNAhttp://repub.eur.nl/pub/56935/
Tue, 13 Apr 2004 00:00:01 GMT<div>L. Jacobs</div><div>R.J. Jongbloed</div><div>F.A. Wijburg</div><div>J.B.C. de Klerk</div><div>J. Geraedts</div><div>J.G. Nijland</div><div>H.R. Scholte</div><div>I.F.M. de Coo</div><div>H.J. Smeets</div>
Pearson syndrome is an often fatal multisystem disease associated with mitochondrial DNA rearrangements. Here we report a patient with a novel mtDNA deletion of 3.4 kb ranging from nucleotides 6097 to 9541 in combination with deletion dimers. The mutation percentage in different tissues (blood, muscle and liver) varied between 64% and 95%. After a remission period of about a year, the patient suddenly died at the age of 3 years owing to a severe lactic acidosis. A second patient with a previously reported deletion of 8 kb and a milder phenotype was found to have mitochondrial duplications and died at the age of 10 years. From these data and data from previous reports, we hypothesize that duplications might be beneficial in the clinical course of the disease and in life expectancy.Long-term intravenous treatment of Pompe disease with recombinant human alpha-glucosidase from milkhttp://repub.eur.nl/pub/10338/
Thu, 01 Jan 2004 00:00:01 GMT<div>J.M.P. van den Hout</div><div>B. Sibbles</div><div>J.P. Brakenhoff</div><div>A.H. Cromme-Dijkhuis</div><div>N. Weisglas-Kuperus</div><div>A.J.J. Reuser</div><div>M. Boer</div><div>J.A. Smeitink</div><div>O.P. van Diggelen</div><div>E. Voort</div><div>E.J. van Corven</div><div>H. van Hirtum</div><div>J.H.J. Kamphoven</div><div>A.T. van der Ploeg</div><div>J. van Hove</div><div>W.F.M. Arts</div><div>P.A. van Doorn</div><div>J.B.C. de Klerk</div><div>M.C.B. Loonen</div><div>A.G. Vulto</div><div>M.A. Kroos</div><div>W.C.J. Hop</div><div>L.P.F. Winkel</div><div>G. de Jong</div>
OBJECTIVE: Recent reports warn that the worldwide cell culture capacity is
insufficient to fulfill the increasing demand for human protein drugs.
Production in milk of transgenic animals is an attractive alternative.
Kilogram quantities of product per year can be obtained at relatively low
costs, even in small animals such as rabbits. We tested the long-term
safety and efficacy of recombinant human -glucosidase (rhAGLU) from rabbit
milk for the treatment of the lysosomal storage disorder Pompe disease.
The disease occurs with an estimated frequency of 1 in 40,000 and is
designated as orphan disease. The classic infantile form leads to death at
a median age of 6 to 8 months and is diagnosed by absence of
alpha-glucosidase activity and presence of fully deleterious mutations in
the alpha-glucosidase gene. Cardiac hypertrophy is characteristically
present. Loss of muscle strength prevents infants from achieving
developmental milestones such as sitting, standing, and walking. Milder
forms of the disease are associated with less severe mutations and partial
deficiency of alpha-glucosidase. METHODS: In the beginning of 1999, 4
critically ill patients with infantile Pompe disease (2.5-8 months of age)
were enrolled in a single-center open-label study and treated
intravenously with rhAGLU in a dose of 15 to 40 mg/kg/week. RESULTS:
Genotypes of patients were consistent with the most severe form of Pompe
disease. Additional molecular analysis failed to detect processed forms of
alpha-glucosidase (95, 76, and 70 kDa) in 3 of the 4 patients and revealed
only a trace amount of the 95-kDa biosynthetic intermediate form in the
fourth (patient 1). With the more sensitive detection method,
35S-methionine incorporation, we could detect low-level synthesis of
-glucosidase in 3 of the 4 patients (patients 1, 2, and 4) with some
posttranslation modification from 110 kDa to 95 kDa in 1 of them (patient
1). One patient (patient 3) remained totally deficient with both detection
methods (negative for cross-reactive immunologic material [CRIM
negative]). The alpha-glucosidase activity in skeletal muscle and
fibroblasts of all 4 patients was below the lower limit of detection (<2%
of normal). The rhAGLU was tolerated well by the patients during >3 years
of treatment. Anti-rhAGLU immunoglobulin G titers initially increased
during the first 20 to 48 weeks of therapy but declined thereafter. There
was no consistent difference in antibody formation comparing CRIM-negative
with CRIM-positive patients. Muscle alpha-glucosidase activity increased
from <2% to 10% to 20% of normal in all patients during the first 12 weeks
of treatment with 15 to 20 mg/kg/week. For optimizing the effect, the dose
was increased to 40 mg/kg/week. This resulted, 12 weeks later, in normal
alpha-glucosidase activity levels, which were maintained until the last
measurement in week 72. Importantly, all 4 patients, including the patient
without any endogenous alpha-glucosidase (CRIM negative), revealed mature
76- and 70-kDa forms of -glucosidase on Western blot. Conversion of the
110-kDa precursor from milk to mature 76/70-kDa alpha-glucosidase provides
evidence that the enzyme is targeted to lysosomes, where this proteolytic
processing occurs. At baseline, patients had severe glycogen storage in
the quadriceps muscle as revealed by strong periodic acid-Schiff--positive
staining and lacework patterns in hematoxylin and eosin--stained tissue
sections. The muscle pathology correlated at each time point with severity
of signs. Periodic acid-Schiff intensity diminished and number of vacuoles
increased during the first 12 weeks of treatment. Twelve weeks after dose
elevation, we observed signs of muscle regeneration in 3 of the 4
patients. Obvious improvement of muscular architecture was seen only in
the patient who learned to walk. Clinical effects were significant. All
patients survived beyond the age of 4 years, whereas untreated patients
succumb at a median age of 6 to 8 months. The characteristic cardiac
hypertrophy present at start of treatment diminished significantly. The
left ventricular mass index decreased from 171 to 599 g/m2 (upper limit of
normal 86.6 g/m2 for infants from 0 to 1 year) to 70 to 160 g/m2 during 84
weeks of treatment. In addition, we found a significant change of slope
for the diastolic thickness of the left ventricular posterior wall against
time at t = 0 for each separate patient. Remarkably, the younger patients
(patients 1 and 3) showed no significant respiratory problems during the
first 2 years of life. One of the younger patients recovered from a
life-threatening bronchiolitis at the age of 1 year without sequelae,
despite borderline oxygen saturations at inclusion. At the age of 2,
however, she became ventilator dependent after surgical removal of an
infected Port-A-Cath. She died at the age of 4 years and 3 months suddenly
after a short period of intractable fever of >42 degrees C, unstable blood
pressure, and coma. The respiratory course of patient 1 remained
uneventful. The 2 older patients, who both were hypercapnic (partial
pressure of carbon dioxide: 10.6 and 9.8 kPa; normal range: 4.5-6.8 kPa)
at start of treatment, became ventilator dependent before the first
infusion (patient 2) and after 10 weeks of therapy (patient 4). Patient 4
was gradually weaned from the ventilator after 1 year of high-dose
treatment and was eventually completely ventilator-free for 5 days, but
this situation could not be maintained. Currently, both patients are
completely ventilator dependent. The most remarkable progress in motor
function was seen in the younger patients (patients 1 and 3). They
achieved motor milestones that are unmet in infantile Pompe disease.
Patient 1 learned to crawl (12 months), walk (16 months), squat (18
months), and climb stairs (22 months), and patient 3 learned to sit
unsupported. The Alberta Infant Motor Scale score for patients 2, 3, and 4
remained far below p5. Patient 1 followed the p5 of normal. CONCLUSION:
Our study shows that a safe and effective medicine can be produced in the
milk of mammals and encourages additional development of enzyme
replacement therapy for the several forms of Pompe disease. Restoration of
skeletal muscle function and prevention of pulmonary insufficiency require
dosing in the range of 20 to 40 mg/kg/week. The effect depends on residual
muscle function at the start of treatment. Early start of treatment is
required.Severe acute necrotizing pancreatitis associated with lipoprotein lipase deficiency in childhoodhttp://repub.eur.nl/pub/73134/
Mon, 01 Sep 2003 00:00:01 GMT<div>L.A. van Walraven</div><div>J.B.C. de Klerk</div><div>R.R. Postema</div>
An 11-year-old girl with lipoprotein lipase deficiency experienced recurring episodes of abdominal pain. She initially underwent appendectomy for suspected appendicitis; however, the appendix was normal. Pancreatitis was subsequently identified as the cause of her pain.Tyrosine hydroxylase deficiency causes progressive encephalopathy and Dopa-nonresponsive dystoniahttp://repub.eur.nl/pub/59967/
Tue, 05 Aug 2003 00:00:01 GMT<div>G.F. Hoffmann</div><div>B. Assmann</div><div>C. Bräutigam</div><div>C. Dionisi-Vici</div><div>M. Häussler</div><div>J.B.C. de Klerk</div><div>D. Naumann</div><div>G.C. Steenbergen-Spanjers</div><div>H.-M. Strassburg</div><div>R.A. Wevers</div>
The natural course of infantile Pompe's disease: 20 Original cases compared with 133 cases from the literaturehttp://repub.eur.nl/pub/63470/
Fri, 01 Aug 2003 00:00:01 GMT<div>H.M.P. van den Hout</div><div>W.C.J. Hop</div><div>O.P. van Diggelen</div><div>J.A.M. Smeitink</div><div>G.P. Smit</div><div>B.T. Poll-The</div><div>H.D. Bakker</div><div>M.C.B. Loonen</div><div>J.B.C. de Klerk</div><div>A.J.J. Reuser</div><div>A.T. van der Ploeg</div>
The natural course of infantile Pompe's disease: 20 original cases compared with 133 cases from the literaturehttp://repub.eur.nl/pub/10199/
Wed, 01 Jan 2003 00:00:01 GMT<div>J.M.P. van den Hout</div><div>A.T. van der Ploeg</div><div>O.P. van Diggelen</div><div>J.A. Smeitink</div><div>G.P. Smit</div><div>B.T. Poll-The</div><div>H.D. Bakker</div><div>M.C.B. Loonen</div><div>J.B.C. de Klerk</div><div>A.J.J. Reuser</div><div>W.C.J. Hop</div>
OBJECTIVE: Infantile Pompe's disease is a lethal cardiac and muscular disorder. Current developments toward enzyme replacement therapy are promising. The aim of our study is to delineate the natural course of the disease to verify endpoints of clinical studies. METHODS: A total of 20 infantile patients diagnosed by the collaborative Dutch centers and 133 cases reported in literature were included in the study. Information on clinical history, physical examination, and diagnostic parameters was collected. RESULTS: The course of Pompe's disease is essentially the same in the Dutch and the general patient population. Symptoms start at a median age of 1.6 months in both groups. The median age of death is 7.7 and 6 months, respectively. Five percent of the Dutch patients and 8% of all reported patients survive beyond 1 year of age. Only 2 patients from literature became older than 18 months. A progressive cardiac hypertrophy is characteristic for infantile Pompe's disease. The diastolic thickness of the left ventricular posterior wall and cardiac weight at autopsy increase significantly with age. Motor development is severely delayed and major developmental milestones are generally not achieved. For the Dutch patient group, growth deviates significantly from normal despite start of nasogastric tube feeding. Levels of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, creatine kinase, or creatine kinase-myocardial band isoenzyme are typically elevated, although aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase increase significantly with age. The patients have fully deleterious mutations. Acid alpha-glucosidase activity is severely deficient. CONCLUSIONS: Survival, decrease of the diastolic thickness of the left ventricular posterior wall, and achievement of major milestones are valid endpoints for therapeutic studies of infantile Pompe's disease. Mutation analysis and measurement of the alpha-glucosidase activity should be part of the enrollment program.Intermediates of unsaturated fatty acid oxidation are incorporated in triglycerides but not in phospholipids in tissues from patients with mitochondrial β-oxidation defectshttp://repub.eur.nl/pub/58650/
Mon, 06 Aug 2001 00:00:01 GMT<div>W. Onkenhout</div><div>V. Venizelos</div><div>H.R. Scholte</div><div>J.B.C. de Klerk</div><div>B.J. Poorthuis</div>